Omics · study · 2026
Small Molecule Disrupts G4-STAT1 Interaction and Synergizes with Olaparib to Drive Cancer Cell Death
Listed in NCBI GEO
Bloom syndrome protein (BLM), a RecQ family DNA helicase, is consistently overexpressed in multiple malignancies, yet its therapeutic potential remains largely unexplored.
Description
Herein, we focused on targeting the BLM promoter G-quadruplex (BLM-G4) to inhibit the BLM signaling pathway. We first characterized the parallel BLM-G4 in BLM promoter region.
Subsequently, it is evidenced for the first time that BLM-G4 recruits phosphorylated STAT1 to activate BLM expression. Importantly, two natural alkaloids, berberine (BER) and coptisine (COP), compete with STAT1 for binding to BLM-G4, thereby significantly suppressing BLM expression in colon cancer cells. The BER/COP-BLM-G4 complex structures were determined using NMR experiments, which provide valuable insights for the rational design of next-generation BLM-G4-targeting ligands.
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Beyond BLM regulation, the conjoint analysis of genome-wide STAT1-CUT&Tag-seq, G4P-CUT&Tag-seq, and RNA-seq demonstrated STAT1 as a general G4-binding transcription factor and COP as a pan-genomic G4 stabilizer. Furthermore, BER/COP exhibited a pronounced synergistic effect with Olaparib in inducing colon cancer cell death by disrupting DNA repair pathways and intensifying DNA damage. Collectively, our findings reveal a novel epigenetic mechanism of BLM gene upregulation mediated by BLM-G4-STAT1 interaction and suggest that the combination therapy of G4 stabilizers with PARP inhibitors is a promising strategy for treating complex cancers.
Links
Get the data
- GEO FTP directory ftp.ncbi.nlm.nih.gov/geo/series/GSE324nnn/GSE324248 ↗
download · from NCBI GEO
Where it is published
- GEO accession page ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE324248 ↗
landing page · from NCBI GEO
Documentation and papers
- PRJNA1433853 ncbi.nlm.nih.gov/bioproject/PRJNA1433853 ↗
project · from NCBI GEO
- PubMed 42087785 pubmed.ncbi.nlm.nih.gov/42087785 ↗
publication · from NCBI GEO
Topics
- Stated by source
- Genome binding/occupancy profiling by high throughput sequencing · Homo sapiens
- From keywords
- Life Sciences
- Inferred from text
- Cancer 75% · RNA sequencing 65%
Provenance · 1 source records, 9 field assertions
| Source | Key | Last seen | Raw |
|---|---|---|---|
| NCBI GEO | GSE324248 | 12 d ago | JSON v1 |
| Field | Assertion | Extractor | Evidence |
|---|---|---|---|
| access_level | source · NCBI GEO | connector:ncbi_geo@1.0.0 | |
| concepts[disease].local:disease:cancer | enrichment · NCBI GEO | keyword-concept-rules@1.0.0 | title+description (75%) |
| concepts[field].local:field:life-sciences | mapping · NCBI GEO | connector:ncbi_geo@1.0.0 | |
| concepts[method].geo_series_type:genome-binding-occupancy-profiling-by-high-throughput-sequencing | source · NCBI GEO | connector:ncbi_geo@1.0.0 | /gdstype |
| concepts[modality].local:modality:rna-seq | enrichment · NCBI GEO | keyword-concept-rules@1.0.0 | title+description (65%) |
| concepts[organism].NCBITaxon:9606 | source · NCBI GEO | connector:ncbi_geo@1.0.0 | /taxon |
| description | source · NCBI GEO | connector:ncbi_geo@1.0.0 | /summary |
| publication_date | source · NCBI GEO | connector:ncbi_geo@1.0.0 | |
| title | source · NCBI GEO | connector:ncbi_geo@1.0.0 | /title |